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The Epigenetic Factor BORIS/CTCFL Regulates the NOTCH3 Gene Expression in Cancer Cells

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The Epigenetic Factor BORIS/CTCFL Regulates the NOTCH3 Gene Expression in Cancer Cells Biochimica et Biophysica Acta 1839 (2014) 813–825 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagrm The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells Michele Zampieri a,b, Fabio Ciccarone a,b, Rocco Palermo c, Samantha Cialfi d, Claudio Passananti e, Sabina Chiaretti a, Daniela Nocchia a, Claudio Talora d, Isabella Screpanti b,d,⁎,PaolaCaiafaa,b,⁎⁎ a Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy b Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy c Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy d Department of Molecular Medicine, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy e Institute of Molecular Biology & Pathology CNR, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy article info abstract Article history: Aberrant upregulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying Received 24 January 2014 mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the Received in revised form 23 June 2014 NOTCH3 promoter region might account for its upregulation in cancer cells. We compared DNA and histone Accepted 24 June 2014 methylation status of NOTCH3 promoter region in human normal blood cells and T cell acute lymphoblastic leu- Available online 28 June 2014 kemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA Keywords: hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 T cell acute lymphoblastic leukemia overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important Oncogene role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell Cancer testis antigen lines derived from several solid tumors overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in Chromatin cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, DNA/histone methylation the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3. © 2014 Elsevier B.V. All rights reserved. 1. Introduction type, tissue context and the member of the Notch receptor family ac- tivated [3,4]. The human neurogenic locus notch homolog protein 3 (NOTCH3) An oncogenic role of NOTCH3 pathway was identified in T cell acute gene encodes the third discovered mammalian member of an evolu- lymphoblastic leukemia (T-ALL), since constitutive expression of the ac- tionary conserved family of transmembrane protein receptors (NOTCH tivated intracellular domain of NOTCH3 (NOTCH3-IC) has been shown 1–4). Notch receptors are strictly required for normal embryonic devel- to induce T-cell neoplasias in transgenic mice [5] and the overexpres- opment and for homeostasis of a variety of adult tissues by controlling sion of NOTCH3 in the vast majority of T-ALL validates this finding in the balance between proliferation versus differentiation of stem and/ humans [6]. or progenitor cells [1,2]. Aberrant NOTCH3 signaling has been also observed in several solid A deregulated Notch pathway has been found to be involved in tumors, where NOTCH3 activation favors cell proliferation, resistance the development of a wide variety of human tumors with either an to apoptotic stimuli, metastatic capability and maintenance of stem oncogenic or a tumor-suppressive role depending on the cancer cell-like features [7]. Moreover, a correlation between NOTCH3 expression and poor prog- fi ⁎ Correspondence to: I. Screpanti, Department of Molecular Medicine, Faculty of nostic outcome has been described in primary tumors thus con rming Pharmacy & Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 NOTCH3 involvement in cancer pathogenesis [8–10]. Rome, Italy. Tel.: 0039(06)44700816. Molecular details of the genetic mechanisms (i.e. gene amplification, ⁎⁎ Correspondence to: P. Caiafa, Department of Cellular Biotechnologies and chromosome translocation) causing NOTCH3 receptor activation as well Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Via Chieti 7, as the consequent activation of signaling are emerging in the context of 00161 Rome, Italy. Tel.: 0039(06)49976530. fi – E-mail addresses: [email protected] (I. Screpanti), [email protected] speci ctumors[11 15], while the causes of NOTCH3 gene overexpres- (P. Caiafa). sion in cancer cells remain poorly understood. http://dx.doi.org/10.1016/j.bbagrm.2014.06.017 1874-9399/© 2014 Elsevier B.V. All rights reserved. 814 M. Zampieri et al. / Biochimica et Biophysica Acta 1839 (2014) 813–825 Epigenetic processes often contribute to the deregulated expression As with respect to PBMCs, the NOTCH3 silencing could be explained of genes critical to the development and progression of cancer. The fact by both the low H3K4me3 and high H3K27me3 amounts. However, this that the transcription start site (TSS) of NOTCH3 localizes within a CpG condition does not depend on the heterochromatization as indicated by island prompted us to investigate a possible correlation between the absence of H3K9me3, whose presence instead characterizes SKW3 NOTCH3 gene DNA methylation status and gene expression extending cells, which do not express NOTCH3. the analysis to histone methylation. We report here that the cancer testis antigen (CTA) BORIS/CTCFL 2.2. CTCF and BORIS differentially occupy NOTCH3 promoter in normal (Brother Of Regulator of Imprinted Sites)/CTCF-like protein), paralog blood cells and T-ALL cell lines of the widely expressed chromatin insulator CTCF (CCCTC-binding factor) [16,17], is involved in the epigenetic deregulation leading to To search for potential trans-acting protein factors responsible for NOTCH3 upregulation in cancer cells. In particular, BORIS presence mir- epigenetic regulation of NOTCH3 gene expression, the Genomatix rors NOTCH3 overexpression specifically in T-ALL established cell lines MatInspector software was used [18,19]. The inspection of as well as in primary T-ALL human samples from patients at the onset about 2000 bp of the NOTCH3 5-prime sequence (transcript ID of the disease. Furthermore, BORIS binding to NOTCH3 promoter is ENST00000263388) revealed the presence of eight regions located associated with histone modifications typical of permissive/active chro- in the proximity of the TSS (from − 391 to +259) which match matin conformation. Overall, our data highlight a key role played by with the CTCF binding sequence (data not shown). Three of them ex- BORIS in the abnormal upregulation of NOTCH3 in cancer cells. hibited a high degree of similarity to CTCF binding sites with a qual- ity rating above the algorithm defined cut off value of 0.8 (Fig. 2A, 2. Results sites 1, 2 and 3). Furthermore, same result was obtained by compar- ing the same region with previously published 20-bp binding motifs 2.1. NOTCH3 gene expression and promoter epigenetic profile in normal for CTCF [20] (Fig. 2B). This was also suggested by ChIP-seq data from blood cells and in T-ALL cell lines the ENCODE consortium accessed through the UCSC genome brows- er (http://genome.ucsc.edu) [21–23] (Supplementary Fig. S1). Whether or not DNA methylation of the NOTCH3 promoter restricts CTCF DNA-target sites could also be bound by CTCFL/BORIS, a CTCF- NOTCH3 expression was investigated. paralog protein that may have epigenetic CTCF-antagonistic regulative NOTCH3 mRNA level analysis was performed by real-time RT-PCR in functions on CTCF binding regions of target genes [17,24–26]. normal blood cells [peripheral blood mononuclear cells (PBMCs), To address whether CTCF and BORIS are both involved in the regula- CD4+ and CD8+ T-lymphocytes] and in T-ALL cell lines differentially tion of NOTCH3 expression, transcript levels of CTCF and BORIS were an- expressing NOTCH3 (MOLT3 and SKW3). Fig. 1A shows that the alyzed by RT-PCR in normal blood cells and T-ALL cell lines, to compare NOTCH3 mRNA level varied significantly with over 500-fold difference their expression with that of NOTCH3 (Fig. 1A). between the lowest and highest expressing cell types (MOLT3 vs. To detect all the 23 known mRNA variants of BORIS [27], its expres- CD8+ T-lymphocytes). High NOTCH3 mRNA levels were found in sion was analyzed by quantitative RT-PCR with two sets of primers MOLT3 cells, while barely detectable NOTCH3 expression characterized encompassing 1–2and3–4 exon boundaries, respectively. SKW3 cells. Notably, low levels of NOTCH3 transcript were detected in CTCF transcript levels were relatively similar in both normal all normal blood cells. blood cells and T-ALL cell lines, irrespectively of NOTCH3 expression The dependence of NOTCH3 expression on DNA methylation of its (Fig. 3A). In contrast BORIS expression appeared to be restricted to T- promoter, colocalizing with a CpG island (Fig. 1B), was investigated by ALL cell lines. However, the presence of BORIS transcript did not corre- bisulfite sequencing in CD4+ T- lymphocytes and in MOLT3 and late
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